REVIEW ARTICLE
Transfusion Therapy in Children With
Sickle Cell Disease
Adlette Inati, MD,* Anthony G. Mansour, MD,w Toni Sabbouh, MD,w
Ghid Amhez, MD,w Ahmad Hachem, MD,w and Hussein A. Abbas, MD, PhDz
Summary: Hydroxyurea, blood transfusions, and hematopoietic
stem cell transplantation represent the 3 disease-modifying thera-
pies in children with sickle cell disease (SCD). Blood transfusions
play an increasingly important role in both prevention and man-
agement of SCD complications in this age group. This review will
focus on the indications of blood transfusion in children with SCD
and modalities of its administration. It will also highlight the
complications of this life-saving therapy and ways of optimizing
transfusion to minimize its associated risks.
Key Words: sickle cell disease, blood transfusion indications, iron
overload
(J Pediatr Hematol Oncol 2017;39:126132)
BACKGROUND
Sickle cell disease (SCD), a monogenic disorder with
multiorgan involvement, involves a structurally abnormal
hemoglobin (Hb) and results in the periodic formation of
sickle-shaped red blood cells (RBCs).1 The 2 main patho-
logic processes behind the clinical manifestations of SCD
are hemolysis and microvascular occlusion.1 Treatment of
SCD consists of health maintenance and preventive meas-
ures, managing acute and chronic complications, and
administration of specic therapeutic options including
hydoxyurea (HU), transfusion therapy, hematopoietic stem
cell transplantation (HSCT), and novel treatment
options.2,3
Transfusion aims to reverse and prevent SCD com-
plications by decreasing the burden of sickled RBCs, sub-
sequently improving oxygen-carrying capacity and perfu-
sion of the microvascular circulation.24 Whereas
transfusion therapy is fundamental to the survival of chil-
dren with thalassemia major, chronic transfusions are pri-
marily used in SCD children with history of stroke or at
increased risk of having a stroke.57 With greater under-
standing of the pathophysiology of SCD-related compli-
cations and ecacy of transfusion therapy in signicantly
decreasing the incidence of stroke, acute chest episodes,
pain events, and need for hospitalization, an increasing
range of indications for transfusions in SCD has now been
identied.8
Received for publication September 20, 2015; accepted June 22, 2016.
From the *Department of Pediatrics, Lebanese American University
and University Medical Center Rizk Hospital, Beirut; wSchool of
Medicine, Lebanese American University, Byblos, Lebanon; and
zDepartment of Molecular and Cellular Oncology, University of
Texas M. D. Anderson Cancer Center, Houston, TX.
The authors declare no conict of interest.
Reprints: Adlette Inati, MD, Department of Pediatrics, Lebanese
American University and University Medical Center Rizk Hospital,
P.O. Box 36, Byblos, Lebanon (e-mail: adlette.inati@lau.edu.lb).
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MODALITIES OF ADMINISTERING BLOOD
TRANSFUSION
Two modalities for administering blood transfusion
have been in use in SCD: simple transfusion and exchange
transfusion. Simple or top-up transfusion entails the infu-
sion of donor RBCs without removal of recipient blood,
whereas exchange transfusion entails removal of recipient
blood during or shortly before donor RBC infusion.
Exchange transfusions can be performed manually or
through an automated method (erythrocytapheresis).
Deciding on the method of transfusion depends on the
patients clinical scenario, institutional expertise and
resources, patient and family preferences, and compatible
blood supply. In acute complications such as acute chest
syndrome (ACS) and/or stroke where Hb S level needs to
be promptly dropped to <30% and Hb level increased to 9
to 10 g/dL, a simple transfusion is indicated for a patient
with Hb level of r5 g/dL, whereas an exchange transfusion
would be more appropriate for a patient with Hb level of
9 g/dL.3,912
The widely available inexpensive chronic simple
transfusion will inevitably lead to iron overload and
hyperviscosity. Chronic exchange transfusion, in contrast,
allows transfusion of donor blood with normal viscosity,
increases the percentage of donor HbA containing RBCs,
and reduces iron overload. Chronic exchange transfusion is,
however, more likely to be associated with a higher inci-
dence of alloimmunization due to multiple donor exposure
and requires expert sta, specialized equipment, permanent
venous access, and higher costs compared with simple
transfusion.3,913
INDICATIONS OF BLOOD TRANSFUSION IN SCD
The use of transfusion therapy in children with SCD is
increasing primarily due to the results of the STOP tri-
als.57,14 Noteworthy, the decision to transfuse SCD
patients should not be based on the childs mere Hb levels
but rather on the childs inability to compensate for the
degree of anemia.3,4,9 By virtue of the decreased oxygen
anity of HbS, RBCs of SCD patients can eciently
deliver oxygen to tissues. This partially explains why chil-
dren with SCD can tolerate chronic anemia despite their
relative low steady-state Hb levels and may not require
transfusions. Hence, transfusion is not indicated in
asymptomatic children with steady-state Hb of 7 to 8 g/dcL
or in those with uncomplicated pain crises or priapism
responding to conservative measures and/or penile aspira-
tion with epinephrine irrigation. Episodic and chronic
transfusions indications are summarized in Table 1 and
further discussed in the next section.2,3,59,1417
J Pediatr Hematol Oncol  Volume 39, Number 2, March 2017
INDICATIONS FOR EPISODIC TRANSFUSION
Acute Anemia Exacerbations
Acute anemia exacerbations in SCD are caused by
acute splenic sequestration (ASS), parvovirus-associated
RBC aplasia, or bleeding.
ASS
ASS, dened as acute splenic enlargement with a drop
in Hb level of at least 2 g/dcL and a normal basal retic-
ulocyte count, is seen in 7% to 30% of children with SCD
in the rst few years of life. ASS is the earliest life-threat-
ening complication besides pneumococcal infections. ASS
can result in shock and death in few hours and can recur in
up to 67% of cases. Because of neonatal screening and early
parental education, mortality rate from ASS has declined in
recent years to 1.8%.18,19 Optimal therapy for ASS has not
yet been dened and randomized prospective trials are
lacking. Immediate packed RBCs transfusion is almost
always indicated for severe cases. Because children with
SCD are adapted to low Hb levels and their RBCs are
viscous, it is important not to exceed Hb of 10 g/dcL by
transfusion to avoid hyperviscosity-associated complica-
tions and clinical deterioration, especially that Hb levels are
expected to further increase as the acute episode
resolves.2,11,18 To correct hypovolemia and to avoid a high
posttransfusion Hb rise, some clinicians suggest the transfer
of small amounts of RBC packs that are given at approx-
imately 5 mL/kg.
Human Parvovirus B19associated RBC Aplasia
Transient RBC aplastic attacks are caused by human
parvovirus B19 infection and present as sudden onset of
severe anemia and reticulocytopenia with fever, abdominal
pain, headache, arthralgias, and erythematous rash. This
condition necessitates immediate packed red blood trans-
fusion. Because anemia may persist for days, close mon-
itoring of Hb posttransfusion is warranted. Spontaneous
reticulocytosis usually occurs in 2 days to 2 weeks
postpresentation.20
ACS
ACS, dened as the presence of abnormal inltrates on
chest x-ray accompanied by fever, chest pain, hypoxia, and
worsening anemia, is the most common cause of death and
the second cause of hospitalization in children with SCD. Its
etiology is multifactorial including vaso-occlusion (VOC),
TABLE 1. Indications for Blood Transfusions in SCD
Episodic transfusions
Acute anemia
Acute stroke
ACS
Acute hepatic sequestration
Multisystemic organ failure
Priapism
Perioperative period
Chronic transfusions
Prevention of primary and recurrent secondary strokes
ACS refractory to hydroxyurea
Pain refractory to hydroxyurea
Severe acute splenic sequestration in children <2 y of age
ACS indicates acute chest syndrome; SCD, sickle cell disease.
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Transfusions in Pediatric SCD
atypical bacterial infections, and pulmonary fat embolism.21
Transfusion of packed RBCs can be an important adjunct
to antimicrobial and supportive therapy in the management
of ACS.22 Simple transfusions are indicated for improving
oxygenation for hypoxic patients, anemia and progression
on chest x-ray, and can decrease morbidity and the usage of
exchange transfusions. Exchange transfusions are indicated
for severe hypoxemia with mild anemia, multilobar disease,
previous history of severe ACS, and cardiopulmonary dis-
ease. The goal of transfusion is to maintain HbS < 30% and
Hb < 10 g/dL.2123 In children with baseline HbZ9 g/dL
and stable respiratory status, simple blood transfusion may
not be required.3
Stroke
Stroke is one of the major complications of SCD
occurring in 11% of patients by the age of 20 years and
have a recurrence rate of 70% within 2 years in untreated
patients.24 The recommended treatment in an acute setting
of overt stroke is exchange transfusions. In a retrospective
cohort study, after the rst stroke, SCD patients who had
exchange transfusions had fewer secondary strokes than the
patients who received simple transfusions only.25
Multisystem Organ Failure Syndrome (MSOF)
MSOF is a severe and life-threatening SCD compli-
cation characterized by lung, liver, and or kidney failure
usually occurring several days following a severe VOC,
typically in patients with no history of chronic organ
damage. Unexpected and quick deterioration often occurs.
Aected children usually have fever, acute respiratory
failure with concomitant ACS, encephalopathy, rapid
decrease in Hb concentration and platelet count, and rapid
increase in serum creatinine, potassium, total and direct
bilirubin, liver enzymes, and blood coagulation tests.
Prompt identication and treatment of MSOF are impor-
tant to prevent death and irreversible sequalae. Treatment
includes immediate simple or exchange transfusion, ven-
tilatory support for respiratory failure, and hemodialysis
for acute renal failure.2,3,7
Prophylactic Perioperative Transfusion
Surgical procedures in SCD can be associated with
multiple postoperative complications including ACS, VOC,
and stroke. Prophylactic transfusions are commonly used in
the perioperative period to prevent the development of such
complications. In the Cooperative Study of Sickle Cell
Diseases (CSSCD), the incidence of postoperative SCD-
related complications in patients with SCD and sickle
hemoglobin C (HbSC) disease was signicantly lower in
those who had preoperative transfusion compared with
those who did not have transfusion.26 Noteworthy, simple
transfusions were equally eective to exchange tranfusions
in reducing the incidence of perioperative complications.27
More recently, the Transfusion Alternatives Preoperatively
in SCD (TAPS) study that randomized 67 patients with
HbSS or HbSb0 subtypes, aged at least 1 year and under-
going low-risk or medium-risk surgery, to either pre-
operative or to no-preoperative transfusion, was halted
prematurely due to signicantly less complications in the
transfusion arm compared with the no-transfusion arm.28
Specically, 39% of patients in the no-preoperative trans-
fusion arm had signicant complications, compared with
15% in the preoperative-tranfusion group (P = 0.023).28
Hence, usage of preoperative transfusions can decrease the
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Inati et al
risk of severe postoperative adverse eects and complica-
tions. More studies are warranted to compare the utility of
simple versus exchange transfusions in decreasing surgical
complications among SCD patients.
Others Indications for Episodic Transfusion
Other signicant indications for episodic transfusions
include acute hepatic sequestration,5,6 acute intrahepatic
cholestasis,2 and acute renal failure.3
INDICATIONS FOR CHRONIC TRANSFUSION
Chronic transfusions decrease the sickle RBC burden
and degree of hemolysis and are eective in reducing many
complications of SCD. The most important indications for
chronic transfusion are described below and summarized
in Table 1. Table 2 represents a summary of the guidelines
proposed by an expert panel to monitor patients on chronic
transfusions.3
Stroke
An abnormal transcranial Doppler (TCD) has been
shown to be predictive of stroke risk (10%/y) in SCD
patients.6 Chronic transfusion is now considered the
standard care for preventing primary and recurrent strokes
and their devastating outcomes in children with SCD.13 The
Stroke Prevention Trial in Sickle Cell Anemia (STOP 1)
clearly demonstrated that chronic transfusion reduced the
risk of stroke by >70% as compared with the risk
accompanied by standard treatment in children with SCD
at high risk of stroke detected by TCD.6,7 STOP 2 recom-
mended to continue transfusion indenitely, even after
TCD velocities are reduced to normal.14 Early TCD
screening and intensication of transfusion therapy can
result in >5 times reduction of stroke risk by 18 years of
age.29 The TWiTCH trial, a multicenter phase III
randomized clinical trial to compare standard therapy
(transfusion) with alternative therapy (ie, HU),
TABLE 2. Consensus Protocol for Monitoring Individuals on
Chronic Transfusion (NIH Expert Panel 2014) (Yawn et al)3
1. Recommended measures at time of starting chronic transfusion
a. Collect information on total number of previous transfusions
and associated adverse events, if any
b. Notify the blood bank that the patient has SCD and request
RBC phenotype, type and antibody screen, quantitative
percentage of HbA and HbS determination, complete blood
count and reticulocyte count
c. Inform the patient if he or she is alloimmunized and advise
him/her/parents to present this information to any
transfusion service he/she seeks
2. Suggested evaluation before each transfusion
a. Complete blood count and reticulocyte count
b. Quantitative determination of percentage of HbA and HbS
(done to conrm that target percent of HbS is achieved)
c. Type and antibody
3. Suggested periodic evaluations
a. Liver function tests annually or semiannually for those with
iron overload
b. Steady-state serum ferritin quarterly
c. Screening for hepatitis C, hepatitis B, and HIV annually
d. Evaluation for iron overload every 1-2 y by liver biopsy or
liver MRI
HIV indicates human immune deciency virus; MRI, magnetic reso-
nance imaging; RBC, red blood cells.
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J Pediatr Hematol Oncol  Volume 39, Number 2, March 2017
demonstrated that HU treatment can substitute for chronic
transfusions for the maintenance of lowered TCD velocities
in pediatric subjects with SCD and abnormal TCD veloc-
ities and help to prevent primary stroke.30,31 For children at
high stroke risk unable or unwilling to undergo regular
transfusions, HU or HSCT need to be considered.30
Chronic transfusions also help prevent the recurrence
of strokes in SCD children based on long-term observa-
tional studies. A high risk of stroke recurrence is evident in
patients who discontinue transfusion therapy.15,32 The
stroke with transfusions switched to HU study (SWiTCH)
compared standard treatment (ie, transfusion/chelation) to
alternative treatment (ie, HU/phlebotomy) in children with
SCD, stroke, and iron overload, and demonstrated that
transfusion was more eective than HU in reducing strokes
in this patient population.33 On the basis of the results of
multicenter randomized trials, more children with SCD are
therefore expected to receive chronic transfusion.
Silent Cerebral Infarcts (SCI)
SCI, dened as the presence of abnormal brain mag-
netic resonance imaging (MRI) in the setting of a normal
neurological examination without a history or physical
ndings associated with an overt stroke, are the most
common neurological injury in children with SCD. SCI
aects approximately 22% of children with SCD and are
associated with the recurrence of an infarct (stroke or SCI)
and neurocognitive dysfunction. Previous studies have
demonstrated the occurrence of silent strokes and cerebral
vasculopathy despite chronic blood transfusions. However,
the recent controlled trial of transfusions for SCI (SIT)
comparing regular transfusions to standard care in children
with SCD and SCI concluded that regular transfusion
therapy resulted in a 58% relative risk reduction of infarct
recurrence when compared with those who did not receive
transfusion therapy. This study also provided the rst evi-
dence that children with SCD receiving regular transfusion
therapy had better overall health-related quality of life and
felt better as reected by the Change in Health measure-
ment scores than those on observation only (dierence
estimate = 0.54, Pr0.001).
Severe ASS in Children Below 3 Years
Chronic RBC transfusion to keep HbS < 30% may be
indicated in children below 3 years of age, who have had a
severe ASS episode until a splenectomy is performed at age
3 years.4,9,34 Chronic transfusions increase baseline Hb level
and decrease the risk of life-threatening anemia in the event
of a future ASS. Nevertheless, chronic transfusions do not
fully prevent recurrence of ASS neither is the rst-line
treatment for severe ASS. Chronic transfusions can be used
as a bridging treatment until the patient can undergo
splenectomy. Indications for splenectomy remain to be
determined, and assessing splenic function and the presence
of an accessory spleen before splenectomy is still recom-
mended. To note, assessing splenic function can be done
through determination of the percentage of pitted eryth-
rocytes and conrmation by 99-Technitium-labeled heat-
altered autologous erythrocytes scintigraphy with multi-
modality single-photon emission computerized tomography
(SPECT) scan.
Refractory Pain
Chronic transfusions may be indicated for children
with severe refractory pain. This indication was elucidated
J Pediatr Hematol Oncol  Volume 39, Number 2, March 2017
from STOP trials, where hospitalization rates for pain were
signicantly lower in the transfused group versus the non-
transfused group (9.7 vs. 27.1 events per 100 patient-years,
P = 0.014), underscoring the benet of chronic transfusion
in minimizing the morbidity associated with this frequent
SCD complication.35
Refractory ACS
Chronic transfusion is indicated for children with
severe refractory ACS. For those who have experienced a
severe ACS episode needing intubation, it may be prudent
to give a short course of chronic transfusion as HU requires
several months to reach maximum benets. In STOP trials,
hospitalization rates for ACS were signicantly lower in the
transfused group versus the nontransfused group (4.8 vs.
15.3 per 100 patient-years, P = 0.0027), underscoring the
benet of chronic transfusion in ameliorating this highly
prevalent and devastating SCD complication.
TRANSFUSION COMPLICATIONS
RBC transfusions are unequivocally lifesaving in
children with SCD. However, transfusions are associated
with multiple complications some of which are relatively
mild, whereas others can be severe and life threatening.
Compared with other populations, children with SCD seem
to be at a higher risk of developing certain complications,
particularly alloimmunization, hyperviscosity, and delayed
hemolytic transfusion reactions (DHTR).2,3 Other compli-
cations include those encountered in other children on
chronic transfusion iron overload, transfusion reactions,
blood-borne infections, and metabolic aberrations.2,3 The
following sections describe the most frequent transfusion-
related complications in children with SCD.
Alloimmunization
Alloimmunization is due to an immunologic response
by the recipient against foreign donor RBC antigens lead-
ing to premature RBC destruction and immune-mediated
clearance. The prevalence of alloimmunization varies from
1% to 30% among dierent populations.3639 In the
CSSCD, which enrolled 3047 patients including 2102 chil-
dren below 19 years of age at entry, the overall rate of
alloimmunization to RBC antigens was 18.6% in the 1814
transfused children compared with only 2% to 5% of all
non-SCD transfusion recipients.40 It is more frequent when
ethnically dierent donors (typically whites) and recipients
(typically African Americans) have dierent RH alleles and
RBC antigenic proles.2,3,16,34,41,42 The rate of alloimuni-
zation increases with increasing number of transfusions
received, older age, SCD genotype, and transfusions during
inammatory events (VOC more than ACS).43 Alloimmu-
nization usually limits the ability to nd compatible blood
for future transfusions and increases risk for DHTR.2,3,34,42
In a recent review, Gardner et al44 described the manage-
ment of DHTR, which mimics acute pain episodes, and can
range from supportive management to immunosup-
pression. On the basis of these ndings, weighing the
advantages of transfusions against the risk of developing
alloimmunization, particularly in patients at high risk, is an
important priority before administering transfusions during
inammatory states.45
The alloantibodies most frequently seen in SCD are
against RBC antigens in the Rh system (C and E) and other
minor blood groups (Kell and Lewis). Extended RBC
antigen matching utilizing hemagglutination methods and
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Transfusions in Pediatric SCD
DNA-based testing of blood group genotypes may decrease
alloimmunization rates. In a recent study comparing
hemagglutination and DNA-based RBC antigen pheno-
typing, the latter method provided superior accuracy and
expanded information on RBC antigens compared with
hemagglutination methods. Authors recommended the
implementation of DNA-based RBC typing as the primary
method for extended RBC typing for patients with SCD at
their institution.46 Whether DNA-based RBC typing will
signicantly reduce Rh alloimmunization in SCD needs to
be further examined.2,3,4143,47 Recent advances in blood
group genotyping can facilitate identication of antigen-
matched RBCs and automated DNA extraction coupled
with database-driven RBC matching may decrease alloim-
munization risk among aected patients. However, its
utility in SCD patients have not been assessed. Further,
such systems require large collaborative eorts and sig-
nicant funding that may not be available for developing
countries where prevalence of SCD is high.
Hyperviscosity
RBC transfusion will increase hematocrit and whole
blood viscosity in SCD and trigger VOC particularly if
given to children with a relatively high baseline Hb. When
this increase in hematocrit is sudden, acute clinical deteri-
oration (ASPEN syndrome, which is characterized by the
association of priapism, exchange transfusion, and neuro-
logical events in SCD patients) may also occur. Using a
target posttransfusion hematocrit of 30% as well as eryth-
rocyte exchange transfusion can minimize hyperviscosity
and its morbid complications. Even though much of the
rheological data supporting relatively lower posttransfusion
hematocrits to prevent increases in whole blood viscosity
were generated in vitro or on a small number of patients,
nonetheless, this recommendation has been judged as
strong according to an expert panel on best practices for
transfusion for patients with SCD.4851
Iron Overload
Iron overload represents a serious and often under-
estimated complication of potentially life-saving blood
transfusions in SCD. Iron overload is seen in 33% of
aected patients with SCD, even in some patients who have
not received transfusions. Because humans have a limited
ability to excrete iron, repetitive transfusions induces
gradual iron level build-up until reaching toxic levels.
Following 20 transfusions (200 to 250 mg iron/1 blood
unit), ferritin levels are expected to increase to a staggering
1000 mg/L; iron accumulates in the liver, heart, and endo-
crine organs, and iron overload symptoms start to mani-
fest.2,4,5254 Patients with iron overload have a higher inci-
dence of pain, organ failure, and death compared with
those who do not have iron overload.55 If not treated, iron
overload will inevitably lead to systemic organ failure.2,4,54
Contrary to thalassemia patients, SCD patients are
often suboptimally monitored for iron overload and studies
that asses iron chelation in SCD are limited.52,56 Never-
theless, proper assessment and monitoring of iron overload
are crucial. Serial measurements of total number of trans-
fusions received and of steady-state serum ferritin can help
estimate the degree of iron loading to some extent. How-
ever, the gold standard in determining degree of iron
overload in SCD as in other transfusion-dependent anemias
remains liver iron quantication. This can be assessed
through validated methods such as MRI R2 or MRI T2*
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Inati et al J Pediatr Hematol Oncol  Volume 39, Number 2, March 2017

and R2* techniques or liver biopsy (when MRI methods are
not available). The optimal frequency of assessment has not
been determined and is usually based in part on the indi-
vidual patients features.2,3,54
Iron chelation therapy is recommended for cumulative
transfusions of 120 mL pRBC/kg or 20 top-up transfusions,
steady-state serum ferritin level >1000 mg/L, and
LICZ7 mg Fe/g dry weight.52,56 Chelator doses should be
tailored to meet individual patient needs and lifestyle
demands. Children receiving iron chelation therapy should
be regularly advised about need for compliance with ther-
apy. Maintaining steady-state ferritin at <1000 ng/mL and
LIC < 3 mg/g liver dry weight is recommended.45,46,57 A
recent review by Porter and Garbowski58 summarized the
trials with iron chelation in SCD. Although most of the
iron chelators were well tolerable, adverse eects included
gastrointestinal disturbances such as diarrhea, vomiting,
abdominal pain, as well as a mild increase in creatinine.58
The 3 known iron chelators, deferoxamine (DFO),
deferiprone (DFP), and deferasirox (DFX), all manage to
bind iron and enhance its excretion preventing iron depo-
sition, but they dier in their bioavailability, plasma half-
life, and metabolism.53 DFO, given by subcutaneous or
intravenous route, leads to iron excretion through both
urine and feces, whereas DFP, the 3 times daily oral che-
lator, is excreted through the urine and requires close
monitoring due to the risk of agranulocytosis. The once-
daily oral chelator DFX removes iron primarily through
the gastrointestinal tract.53 Over 1 year, DFX has been
shown to have similar ecacy to DFO in reducing iron
burden in patients with SCD aged 2 years and above with
transfusional iron overload, dened as having received
Z120 mL/kg of packed RBCs, or LICZ7 mg Fe/g dry
weight, serum ferritin levels Z1000 ng/mL, and body
weight Z10 kg. The long-term safety and ecacy of DFX
have been also well documented for up to 5 years.59,60
Infections
Bacterial contamination of blood products (typically
gram-negative organisms in RBC components) results from
the skin, air and blood collection equipment, and can lead
to sepsis and signicant morbidity and mortality. Viruses
such as human immune deciency virus (HIV), hepatitis B
virus (HBV), hepatitis C virus (HCV), and West Nile virus
can be transmitted through blood as well and can cause
seroconversion in the recipient.61,62 The most fatal blood-
transmitted infection, Creutzfeldt-Jakob disease, leads to
brain damage.63 Prevention entails taking a detailed donor
history, proper donor screening for pathogens, leukocyte
reduction, meticulous preparation of donor phlebotomy
site, and visual inspection of the blood component before
transfusions.62,63
Other Transfusion-related Complications
Hypothermia
RBCs are stored at 41C and if transfused without
warming, especially in large amounts, can lower the core
body temperature leading to impairment in homeostasis,
especially in oxygen transport. Treatment involves warming
up blood using special blood warmers before admin-
istration, and heating the body by warm blankets.64
Citrate and Potassium Toxicity
High amounts of citrate in donor blood can bind to
calcium and magnesium leading to hypocalcaemia and
hypomagnesaemia ending up with cardiac and liver fail-
ure.65,66 To prevent such toxicity, citrate dosages should be
stopped until all citrate is metabolized and electrolyte dis-
turbances are corrected. In contrast, the storage and irra-
diation of RBCs can increase the rate of potassium leakage
leading to hyperkalemia, particularly during rapid trans-
fusion.67 Thus, managing rate of transfusion, age of the
transfused blood, as well as electrolyte disturbances are
important.68

Transfusion Reactions FUTURE RECOMMENDATIONS

Reactions to transfusions can vary from mild to life
threatening and include acute hemolytic transfusions,3,36,37
DHTR,3,38,56,59 allergic and anaphylactic reactions,3,36 and
lung injury.39 Table 3 is a descriptive summary of these
reactions.39,40
As our understanding of the various pathophysio-
logical mechanisms of SCD is improving and as children
with SCD are having a longer life span, the indications for
transfusion therapy in SCD are expanding. Transfusion
therapy can signicantly decrease stroke recurrence and can

TABLE 3. Description, Diagnosis, and Management of Common Transfusion Reactions

Reaction Description Diagnosis Management
Acute Immune mediated primarily due to Fever, chills, pain, hypotension, Transfusion cessation and aggressive
hemolytic incompatible blood type uncontrolled bleeding due to management of hypotension
reaction disseminated intravascular
coagulopathy
Delayed Life threatening usually 5-10 d Often mistaken for vaso-occlusion. Withhold further transfusions. If
hemolytic posttransfusion. Alloantibodies and Fever, pain, hematuria. Can manifest necessary, give transfusions with
transfusion rarely autoantibodies mediated as ACS and adrenal insuciency steroids and intravenous
reaction immunoglobulins
Allergic and Because of antigenic components in Mild itching and hives. Anaphylactic Antihistamines and/or adrenaline shot
anaphylactic transfused blood shock may ensue
reactions
Lung injury Lung inammation within 6 h of Dyspnea Ventilatory support
transfusion
ACS indicates acute chest syndrome.

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J Pediatr Hematol Oncol  Volume 39, Number 2, March 2017
manage a broad spectrum of acute and chronic complica-
tions of SCD. Silent Cerebral Infarct Transfusion (SIT)
trial is one of the major and recent trials to show a 56%
decreased relative risk of cerebrovascular accidents in the
SCD children group, who were being transfused compared
with nontransfused patients over 3 years.69 The availability
of safer blood due to advances in donor selection and pheno-
type matching and of eective and safe oral iron chelators
further encouraged physicians to use blood transfusion. It is
now estimated that around 50% of children and with SCD
would have received at least 1 or more blood transfusion in their
pediatric life time.17 Nevertheless, transfusion therapy is still
associated with several challenging complications. Judicious
application of transfusion guided by sound scientic evidence in
certain clinical situations and weighing risks and benets of this
eective but potentially risky therapy needs to be emphasized to
all SCD health care providers. The use of sickle cell negative,
leucoreduced, phenotypically matched blood in all children with
SCD, and irradiated blood for potential HSCT candidates
reduces febrile reactions, alloimmunization, and cytomegalovi-
rus transmission.2,3,16 Avoidance of hypertransfusion (target Hb
>10 g/dL) in those at risk for hyperviscosity (high percentage of
HbS-containing RBCs) and maintaining a HbS level <30% in
chronically transfused children are additional transfusion pri-
orities in SCD.2,3 Also, health care providers should be wary of
iron overload in SCD patients.
The practicality of applying transfusions outside the set-
ting of a controlled clinical trial remains to be addressed.55
Specically, concerns regarding alloimmunization, intravenous
accessibility in pediatric population, inadequacy of resources in
developing regions, immediate access to blood products when
needed are among the concerns that require more study and
analysis. Further, the concern of the aforementioned compli-
cations of transfusions remains to be addressed to assess
whether the benets overweigh the complications. More
importantly, transfusion therapy has been eective in reducing
morbidity and mortality in developed countries, but it has
lagged behind in the more developing countries where SCD is
most frequent because there is paucity of specialized centers,
medical expertise, resources, and blood supply.
Further research is needed to dene, rene, and opti-
mize treatment protocols to maximize ecacy and minimize
morbidity of transfusion in children with SCD and to
encourage therapeutic approaches, which deal with the
multiple side eects of transfusion. Other therapies aiming
at replacing transfusion with novel and more eective
treatments including HSCT, gene therapy, and agents tar-
geting the various pathophysiological mechanisms of SCD
are still warranted.
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